Hypoxia contributes to reduced fetal growth in major pathological conditions such as intrauterine growth restriction (IUGR) and preeclampsia. Research thus far has failed to develop a means by which these severely compromised pregnancies can be detected early nor has it revealed the specific mechanisms by which hypoxia leads to fetal growth restriction. We have used a unique human model of chronic (altitude-induced) hypoxia to show that despite a substantial decrement in maternal arterial oxygen tension, hypoxia is not the proximate cause of the fetal growth restriction; oxygen delivery to the placenta and fetus is not reduced and fetal oxygen consumption is unaffected. Instead, it is fetal circulating glucose concentrations, fetal glucose consumption and fetal insuli levels that are significantly reduced. These in vivo findings point to excess placental glucose consumption, reducing transfer to the fetus, as an initiating step in fetal growth restriction. Metabolic reprogramming, also known as oxygen sparing appears to be the underlying cause, a phenomenon in which hypoxia actively and reversibly inhibits oxidative metabolism and oxygen consumption through alterations mediated by the Hypoxia-Inducible Factor-1 (HIF-1) transcription factor. Our in vivo data supports that metabolic reprogramming is crucial for ensuring fetal survival, but at the expense of growth. It occurs prior to the operation of the othe factors contributing to fetal growth restriction. Identification of the means by which hypoxia initiates reduction in fetal growth will permit development of diagnostic tests and ameliorative therapies for use, prior to irreversible fetal compromise. As a part of our continuing studies we wish to develop a murine model in which placental metabolic reprogramming mechanisms and the resultant effects on fetoplacental growth can be identified and tested in vivo. In this application we propose to develop a murine model for inducible, placenta-specific HIF-1 knockdown. We will target HIF-1 since it is the regulatory nexus for all metabolic reprogramming mechanisms described thus far. To restrict knockdown to the placenta, we will take advantage of a recently described technique for lentiviral transduction to deliver HIF-1shRNAmir to the outer cell layer of the blastocyst but not the inner cell mass, leading to placental transduction without effects on the fetus. To avoid the embryonic lethality which has complicated previous (systemic) HIF-1 knockdown studies, we will use an inducible vector, allowing us to inhibit placental HIF-1 hypoxic responses at physiologically relevant time points in pregnancy, once major structural development is complete. We will develop this model through the following aims: (1) developing the lentiviral tools for knock down of murine HIF-1 and (2) testing an in vivo model for placental knockdown of HIF-1 using lentiviral transduction of HIF-1 shRNAmir. Development of this model will have a significant impact on studies of fetal hypoxia and growth.